Fatty acids are catabolized, mostly, in the mitochondria through the β-oxidation pathway, where the carnitine palmitoyltransferase (CPT) system plays a key role in transporting long chain fatty acids (FAs) from the cytoplasm to the mitochondrial matrix. The CPT enzymatic system includes the members CPT1A and CPT1B, which are localized in the outer mitochondrial membrane, and CPT2, localized to the inner mitochondrial membrane. While CPT2 seems to be found in the mitochondrial membranes, regardless of the location of the organelle, the CPT1 isoforms have been found to vary with tissue. CPT1A occurs in the liver and CPT1B has been found in muscle. A new protein having sequence homology with CPT1 has been recently identified and given then name CPT1C.
Applicants described in a co-pending U.S. Provisional Application No. 60/893,649, filed on Mar. 8, 2007 (the entire teachings of which are incorporated herein by reference), that CPT1C is a determinant of cell growth and survival, in particular under hypoxic conditions, such as in a tumor in which the cells are rapidly dividing to the point where hypoxic conditions develop locally in the patient tissue: (a) CPT1C has been found to be up-regulated transcriptionally by p53 in vitro and in vivo; (b) depletion of CPT1C in mouse embryonic (ES) stem cells using a gene-trap was found to result in a decrease of cell proliferation, a smaller cell size and a spontaneous activation of the intrinsic mitochondrial apoptosis pathway evidenced by reduced mitochondrial membrane potential and increased caspase activation; (c) CPT1C-deficient mouse ES cells were more sensitive to glucose deprivation or hypoxia, a condition widely observed in tumors; (d) examination by electron microscopy showed swelling of the mitochondria of the CPT1C-depleted ES cells and lipid droplets in the cell, neither being present in the ES cells heterozygous for CPT1C; (e) CPT1C expression was shown to increase in human breast, lung and colon cancer cells lines subjected to hypoxic conditions; (f) CPT1C mRNA levels were measured in paired tumor and matched normal tissues and found to be increased in 15 out of 19 of the lung tumor tissues examined; and (g) growth of human cancer cells in which CPT1C expression was knocked down by small interference RNA was inhibited and further reduced under hypoxic conditions.
In addition, Applicants described in a co-pending U.S. Provisional Application No. 60/893,999, filed on Mar. 27, 2007 (the entire teachings of which are incorporated herein by reference), that CPT1A expression is increased in a large portion of lung tumor tissues compared to normal lung tissues, and that molecular depletion or pharmacological inhibition of CPT1A leads to cell death and growth inhibition of cancer cells.
Therefore, agents which inhibit CPT1, in particular, CPT1A and/or CPT1C, have the potential to treat conditions associated with altered fatty acid metabolism. There is a need for additional agents which can act as glucosylceramide synthase inhibitors.